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Reducing the Unintentional Impact of Triazole Fungicides on Aspergillus fumigatus: Are Cyclodextrins a Solution?

Author(s): Chloé Godeau, Nadia Morin-Crini, Éva Fenyvesi, Fatemeh Haghighi, Marc Fourmentin, Laurence Millon, Christophe Ramseyer, David Landy, Grégorio Crini, Steffi Rocchi

Graphical Abstract

Triazoles are among the most widely used fungicides in agriculture, for the protection of materials and crops. Their broad spectrum of action makes them the substances of choice for preventing and curing fungal diseases such as Septoria or Fusarium wilt. However, their spread in the environment can lead to the selection of triazole resistance not only in crop pathogens, but also in non-target organisms, such as a non-phytopathogenic fungus Aspergillus fumigatus. This fungus is an opportunistic human pathogen associated with high mortality in cases of resistance to pharmacological treatments based on triazoles. There is therefore a need to find ways of limiting the unintended impact of fungicides on this pathogen. We describe here the impact of linear (maltodextrin) or cyclic (cyclodextrins, CDs) dextrins and their interaction with two fungicides (difenoconazole and tebuconazole), through measurements of growth in 20 A. fumigatus strains. Three native (α-CD, β-CD and γ-CD) and two modified (hydroxypropyl-β-CD (HP- β-CD) and heptakis-(2,3,6-tri-O-methyl)-β-CD (TRIMEB)) cyclodextrins were used. In each experiment, the minimum inhibitory concentration (MIC) was determined according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method. Microscopical observations were also performed to highlight the effect of the presence of dextrins. HP-β-CD was the most effective cyclic dextrin. It reduced the antifungal activity of triazoles, whereas maltodextrin and α-CD had no effect. Those observations were more investigated thanks to molecular modeling in order to clarify cyclodextrin/fungicide interactions. The use of cyclodextrins is a promising approach for limiting the emergence of resistance to triazole antifungal drugs.

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